Nicotinic acetylcholine receptors in neurological and psychiatric diseases

Selective Potentiation of the (α4)3(β2)2 Nicotinic Acetylcholine Receptor Response by NS9283 Analogues

“…R f values are given for guidance. 1 H and 13 C NMR spectra were recorded at 300 and 75 MHz using an FT-NMR spectrometer. Chemical shifts are reported in ppm relative to residual solvent (CHCl 3 , MeOH, or DMSO) as internal standard.…”

“…Its implication in drug and nicotine addiction and in a range of severe central nervous system (CNS) disorders is widely documented, and partial α4β2 agonists are currently used as smoking deterrents and investigated for their therapeutic potential in the treatment of depressive symptoms, pain modulation, and reduction of ethanol consumption. 1,2 Relying on previously identified and characterized hits, and on available 3D structures of nAChR subtypes, our work has focused on developing partial agonists selective for α4β2 nAChR. 3−6 Partial agonists of α4β2 nAChR are more suitable for clinical application than full or superagonists due to their wider therapeutic range and attenuated side effects.…”

“…The α4β2 nicotinic acetylcholine receptor (nAChR) is the most abundant subtype in the brain. Its implication in drug and nicotine addiction and in a range of severe central nervous system (CNS) disorders is widely documented, and partial α4β2 agonists are currently used as smoking deterrents and investigated for their therapeutic potential in the treatment of depressive symptoms, pain modulation, and reduction of ethanol consumption. , …”

New Multitarget Molecules Derived from Caffeine as Potentiators of the Cholinergic System

“…In the central nervous system, it is involved in growth, development, and aging-regulating neural plasticity, differentiation, proliferation, and clearance of aged neurons . It is also involved in a large variety of pathophysiological conditions, such as different myasthenic syndromes, myasthenia gravis, in particular, Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder in the elderly characterized by progressive cognitive decline, Tourette syndrome, and nocturnal frontal lobe epilepsies, among others. − Although the occurrence of these different pathophysiological conditions is due to different causes–multifactorial events in some cases–from a therapeutic point of view, they can be classified into two main groups. One group includes the first two above-mentioned pathological conditions, among others, sharing the “cholinergic hypothesis” that is related to a deficit of functional nAChR, and hence nAChR function potentiation is the therapeutic goal (muscle nAChR in the case of myasthenic syndromes and neuronal nAChR for AD, becoming α7 nAChR increasingly more important for AD pathology).…”

Discovery of a Novel Class of Benzimidazole-Based Nicotinic Acetylcholine Receptor Modulators: Positive and Negative Modulation Arising from Overlapping Allosteric Sites

“…The fast cholinergic transmission is mediated by the nicotinic acetylcholine receptors (nAChRs). The receptors are excitatory, cation-selective members of the pentameric ligand-gated ion channel (pLGIC) superfamily, which also contains the 5-HT 3 serotonin, γ-aminobutyric acid A , and glycine receptors (5-HT 3 Rs, GABA A Rs, and GlyRs, respectively). − The 16 human nAChR subunits assemble into highly heterogenous populations of homo- and heteropentameric complexes in vivo , with the neuronal α2−α7, α9−α10, and β2−β4 subunits forming a multitude of different subtypes in the CNS. − , The major neuronal subtypes α4β2 and α7 and the major ganglionic subtype α3β4 are abundantly distributed throughout the CNS, where they as the major mediators of the fast central cholinergic neurotransmission govern a wide range of neuronal functions, − ,− whereas minor nAChR subtypes such as α6β2β3*, α6β4*, and α9* (the asterisks indicate the possible presence of other subunits in the receptors) are expressed in fewer regions and thus mediate more discrete brain functions. − Neuronal nAChRs have been pursued as putative drug targets within neurodegenerative, cognitive, and psychiatric disorders for decades, but so far, the potential in them for these indications cannot be claimed to have been realized.…”